Neuropathological and amyloid peptide differences between DS and familial AD with duplications and missense mutations in APP gene

阿尔茨海默病（AD）是一种神经退行性疾病，其特征是淀粉样斑块的存在，淀粉样斑块主要由脑实质中的细胞外淀粉样β肽（Abeta）沉积物和由过度磷酸化的tau蛋白组成的神经元内神经原纤维缠结组成。此外，β可以作为脑淀粉样血管病（CAA）沉积在血管壁上，这是脑出血的主要原因。虽然在所有AD病例中，包括散发性、家族性和唐氏综合征（DS， 21号染色体三体，Hsa21上淀粉样前体蛋白（APP）基因过量），死后大脑中淀粉样斑块的存在是常见的，但CAA在具有APP重复或某些（但不是全部）点突变的家族性病例中更为突出。APP引起AD的病理和临床差异的性质和机制尚不清楚。我们提出了一项独特的研究，专门针对罕见和研究不足的患者群体，专注于罕见和研究不足，但可能非常有用的患者群体-那些具有APP突变和重复和DS的患者群体-来阐明可能为治疗提供重要线索的差异。我们计划通过研究人类病例、新型小鼠模型以及再生各种疾病的iPSC系衍生的几种细胞类型中的内溶酶体改变和Abeta物种神经病理差异，来研究与APP基因改变多样性相关的临床和神经病理表型的多样性，以揭示与特定Abeta沉积相关的病理生理机制。

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of amyloid plaques mainly constituted of extracellular amyloid beta peptides (Abeta) deposits in brain parenchyma and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau protein. Additionally Abeta can be found deposited in blood vessel walls as cerebral amyloid angiopathy (CAA), a major cause of intracerebral hemorrhage. While the presence of amyloid plaques in postmortem brains is common to all AD cases including sporadic, familial and Down syndrome (DS, trisomy of chromosome 21, with overdose of the Amyloid Precursor Protein (APP) gene on Hsa21), CAA is a more prominent phenotype in familial cases with either APP duplication or certain (but not all) point mutations. The nature and mechanisms underlying these pathological and clinical differences between APP causes of AD remain unclear. We propose a unique study specifically focusing on rare and poorly studied patient groups focusing on rare and poorly studied, but potentially very informative patient groups - those with APP mutations and duplications and DS - to elucidate differences that may provide important clues for treatment. We plan to investigate the diversity of clinical and neuropathological phenotypes associated with the diversity of alterations in the APP gene by studying endo-lysosomal alterations and Abeta species neuropathological differences in human cases, novel mouse models, and in several cell types derived from iPSC lines reproducing various diseases to unravel pathophysiological mechanisms involved in specific Abeta deposition.